Journal of
Personalized
Medicine
Review
Cerebral Oxygen Delivery and Consumption in Brain-Injured
Patients
Dorota Siwicka-Gieroba 1, * , Chiara Robba 2,3 , Jakub Gołacki 1 , Rafael Badenes 4
Citation: Siwicka-Gieroba, D.; Robba,
C.; Gołacki, J.; Badenes, R.;
Dabrowski, W. Cerebral Oxygen
Delivery and Consumption in
Brain-Injured Patients. J. Pers. Med.
2022, 12, 1763. https://doi.org/
10.3390/jpm12111763
Academic Editors: Manuel
V. Granell-Gil, Juan P. Cata and
Eduardo Tamayo
Received: 27 August 2022
Accepted: 17 October 2022
Published: 25 October 2022
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Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
J. Pers. Med. 2022, 12, 1763. https://doi.org/10.3390/jpm12111763
and Wojciech Dabrowski 1
1 Department of Anaesthesiology and Intensive Care, Medical University in Lublin, 20-954 Lublin, Poland
2 Department of Anesthesiology and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology
and Neurosciences, 16132 Genoa, Italy
3 Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, 16132 Genoa, Italy
4 Department of Anesthesiology and Surgical-Trauma Intensive Care, Hospital Clinic Universitari,
University of Valencia, 46010 Valencia, Spain
* Correspondence: dsiw@wp.pl
Abstract: Organism survival depends on oxygen delivery and utilization to maintain the balance of
energy and toxic oxidants production. This regulation is crucial to the brain, especially after acute
injuries. Secondary insults after brain damage may include impaired cerebral metabolism, ischemia,
intracranial hypertension and oxygen concentration disturbances such as hypoxia or hyperoxia.
Recent data highlight the important role of clinical protocols in improving oxygen delivery and
resulting in lower mortality in brain-injured patients. Clinical protocols guide the rules for oxygen
supplementation based on physiological processes such as elevation of oxygen supply (by mean
arterial pressure (MAP) and intracranial pressure (ICP) modulation, cerebral vasoreactivity, oxygen
capacity) and reduction of oxygen demand (by pharmacological sedation and coma or hypothermia).
The aim of this review is to discuss oxygen metabolism in the brain under different conditions.
Keywords: brain; oxygen; delivery; consumption; TBI
1. Introduction
Organism survival depends on oxygen delivery and utilization to maintain the balance
of energy and toxic oxidants production [1]. This regulation is crucial to the central
nervous system (CNS). Brain tissue presents a peculiarly dynamic consumption of energy.
The most productive metabolic process of energy analogs is oxidative phosphorylation,
relating to oxygen consumption [2]. Already in 1890, Roy and Sherrington observed that
increased neuronal activity elevates energy consumption and compensatory metabolic and
vasculature reactions, which in turn improve the functionality of neurons [3]. Therefore,
the oxygen level in cerebral tissue is a crucial element that impacts nerve and glial cell
functions [2].
Brain injury is a common cause of morbidity and mortality worldwide, especially in
the young population [4]. Secondary brain damage occurs in the hours, days or weeks after
an event, and is associated with fatal outcomes [5]. Secondary insults may be mediated by
impaired cerebral metabolism, ischemia, intracranial hypertension and oxygen concentra-
tion disturbances such as hypoxia [6,7]. The combination of hypoxia and hypotension is
associated with enormously high mortality rates [8]. Recent data highlight the important
role of clinical protocols in improving oxygen delivery and resulting in lower mortality
in traumatic and nontraumatic brain-injured patients [9,10]. Clinical protocols guide the
rules for oxygen supplementation based on physiological processes such as increased
oxygen supply (by monitoring of mean arterial pressure (MAP) and intracranial pressure
(ICP), cerebral vasoreactivity and oxygen capacity) and reduction of oxygen demand (by
pharmacological sedation and coma or hypothermia) [11]. Therefore, monitoring oxygen
concentrations such as brain tissue oxygen (PbtO2 ) is an important aspect of brain injury
https://www.mdpi.com/journal/jpm
J. Pers. Med. 2022, 12, 1763 2 of 20

clinical practice [12]. In addition, monitoring of mean arterial pressure and oxygenation of
both local and global tissues are essential for oxygenation and final outcomes [13].
The aim of this review is to discuss oxygen metabolism in the brain under
different conditions.

2. Oxygen Delivery and Autoregulation

The weight of the brain is only 2% of the human body, but cerebral tissue uses
25% of the glucose and about 20% of the oxygen delivered to function normally [14].
Oxygen consumption is 3.5 mL of oxygen/100 g tissue/1 min; therefore, the regulation
of blood flow and delivery of oxygen to cerebral tissue is crucial for brain function [15].
Importantly, 75–80% of the energy consumed by neurons is used at the synapses to restore
the neuronal membrane potentials lost during depolarization [16]. The continuous supply
of oxygen to the brain occurs via arterial blood and is transported to brain tissue by
diffusion. Diffusion is linked to the oxygen conductivity of cerebral tissue, determined
by the geometry of capillaries (distance and area) and the metabolism of tissue (oxygen
gradient from capillary to tissue) [17]. Extraction of oxygen is inversely proportional to
blood flow (when metabolism is constant) and directly proportional to metabolism (when
flow is constant) and the area between tissue and capillaries. Thus, a reduction in oxygen
delivery increases oxygen extraction. It should be noted that when cerebral blood flow
(CBF) is reduced by 50–60%, the consequent elevation of oxygen extraction is insufficient
to maintain proper cerebral oxygenation and a constant cerebral metabolic rate of oxygen
(CMRO2) [18]. Thus, cerebral oxygen delivery is determined by blood oxygen content and
cerebral blood flow. In physiological conditions, total blood flow in the brain is constant
because of the contribution of the large arteries to vascular resistance, as well as the impact
of the parenchymal arterioles on considerable basal tone.
Autoregulation of cerebral blood flow is the mechanism that enables the brain to
maintain relatively constant blood flow through changes in perfusion pressure [19]. In
a normotensive, physiological state, the ensuing cerebral perfusion pressure (CPP) is in
the range of 60 to 160 mmHg, and CBF is maintained at 50 mL per 100 g of brain tissue
per minute. Outside of this range, autoregulation is lost, and CBF starts to be dependent
on MAP in a linear mode [20]. A drop of CPP below the lower limit of 50 mmHg results
in cerebral ischemia [21]. This reduction of CBF is compensated for by elevated oxygen
extraction from the blood.
The individualization of care by targeting optimal, near to cerebral autoregulation
(CA)-guided CPP is connected with improved outcomes in TBI patients [22]. It is worth
remembering that combined brain tissue oxygen with ICP/CCP-guided therapy strongly
ameliorates favorable long-term outcomes [23]. In addition, in a recent meta-analysis, Xie
et al. documented that this combined therapy did not present any effects on mortality,
ICP/CPP and length of stay of patients after TBI [23].
Over a physiological range of partial oxygen pressure (PaO2 ) (75–100 mmHg;
7–13.33 kPa), PaO2 has little effect on global CBF as long as it does not fall below 50 mmHg
(6.67 kPa). This is because CBF is connected to the arterial content of oxygen rather than
PaO2 . The form of the hemoglobin–oxygen dissociation curve indicates that the arterial
content of oxygen is comparatively stable over the discussed PaO2 range [24].
The primary gradient determining the oxygen level in the brain may be enhanced by
a gradient-independent mechanism of cerebral vessel tone changes and increases in CBF
during functional neural activation (neurovascular coupling) [25,26]. The main role of this
mechanism is to transport higher levels of oxygen in advance of the elevated consumption
during neuronal activation [27].
Impairment of cerebral perfusion and metabolism following brain injury has been
documented repeatedly. Unfavorable outcomes after brain injury are connected with
hypoperfusion and decreased glucose metabolism and CMRO2 [28]. Recent data have
documented a connection between CMRO2 and Glasgow Coma Score (GCS) after traumatic
brain injury [29–32]. Soustiel et al. demonstrated that in TBI patients, CBF is somewhat
J. Pers. Med. 2022, 12, 1763 3 of 20

reduced during the first 24 h, and greater hypovolemia is observed following poor outcomes.
Importantly, a decrease in CMRO2 and the cerebral rate of glucose metabolism (CMRG)
correlates with worse outcomes [32].

3. Oxygen Consumption
Oxygen is transported to the cerebral cells by blood diffusion from the capillary to the
mitochondria, until it is consumed in the mitochondria as part of oxidative metabolism.
CMRO2 is the rate of consumption and energy homeostasis in the brain and in healthy,
awake people, averages 3.3 mL/100 g/min [33]. It is related to CBF. Under elevated
metabolic demand, the cerebral vasculature dilates to supply an appropriate increase
in CBF.
Importantly, with elevated neural activity, CMRO2 also rises [34,35]. In a normal,
unstimulated brain, energy is mostly provided by glucose oxidation. Nevertheless, the
metabolic rates of the oxygen-to-glucose ratio, CMRO2 /CMR(glc), called the oxygen-to-
glucose index (OGI), increase during activation and diverge from the textbook value of
6. In addition, the levels of lactates in the brain increase during sensory (e.g., visual)
stimulation [34]. This oxidative metabolism yields more energy as compared to glycolysis,
but precise measurements of this process are limited [36]. Mitochondria present a high
metabolic activity and a critical role in aerobic energy production, and their main function
is the production of adenosine triphosphate (ATP) through oxidative phosphorylation.
Mitochondrial dysfunction is a major factor in the occurrence of cell damage. Suc-
cessful resuscitation during ischemia/reperfusion demands the reestablishment of aerobic
metabolism by reperfusion of oxygenated blood. Mitochondria play a fundamental role as
effectors of reperfusion injury. Damage to the organelle impairs oxidative phosphorylation
and elimination of cytochrome c in the cytosol. The main mechanisms are oxidative stress
and Ca2+ overload [36].
Disturbances in oxygen delivery stop electron flow and interrupt the generation of the
“proton motive force” important in ATP production mentioned above. Of course, cells may
produce ATP anaerobically by glycolysis. However, this process is less effective, insufficient
for metabolic demands, and the final products are lactates.

4. Oxygen in the Cells

The role of mitochondria is to maintain maximal levels of ATP in the physiological
range of oxygen. It is important to remember that there are also other mechanisms responsi-
ble for oxygen consumption. Mostly, O2 is consumed by mitochondria, but 1–2% of oxygen
is incompletely reduced to superoxide anion (O2−) (Figure 1).

Figure 1. “Mitochondrial respiration” benefits when reducing nicotinamide adenine dinucleotide (NADH)
J. Pers. Med. 2022, 12, 1763 4 of 20

and flavin adenine dinucleotide (FADH2 ) components are created by the tricarboxylic acid (TCA)
cycle. In the inner mitochondrial membrane, electrons generated from NADH and FADH2 are
oxidized to NAD+ and FAD+ by complexes I and II. Afterward, these electrons are transferred
successively to complex III, cytochrome c and complex IV. Cytochrome c oxidase (COX, complex IV)
transmits electrons to molecular oxygen. This is an important enzyme in the mitochondrial electron
transport chain (ETC) connecting oxygen with oxidative phosphorylation [37]. The transmission of
electrons through the ETC is connected with proton transfer from the mitochondrial matrix, across
the inner membrane to the intermitochondrial membrane space. This translocation develops an
electrochemical gradient of protons (pH gradient and membrane potential). These molecules may drift
through the F1Fo-ATP synthase (complex V) or back to the mitochondrial matrix [38]. Importantly,
complex V connect protons transfer to the production of ATP from adenosine diphosphate (ADP)
and phosphate. Under normal oxygen levels, pyruvate, as a product of glycolysis, is transported
into the mitochondria, and is transformed into acetyl-CoA by the pyruvate dehydrogenase (PDH)
complex [39]. Afterward, acetyl-CoA connects with oxaloacetate and creates citrate—the first step in
the tricarboxylic acid cycle. Reducing equivalents in this cycle impacts ETC to production of ATP and
reactive oxygen species (ROS) for signaling, and the intermediates of TCA are used for biosynthetic
processes such as lipid synthesis [40].

Organisms develop important adaptation mechanisms [1]. One of these mechanisms

is metabolic suppression. Reduction of mitochondrial oxygen consumption in cells is
observed in oxygen levels between 1 and 3% in vitro. “Oxygen conformance” occurs
when the oxygen (<0.3%) level begins to limit the cytochrome c oxidase (COX) (complex
IV) [37]. Hypoxia, as a result of limited oxygen accessibility, results in reduction of oxidative
phosphorylation and loss of resynthesized phosphates, ATP and phosphocreatine. The
ATP-dependent Na/K pump is also changed and promotes the influx of Na, Ca and water
into cells, causing cytotoxic edema. In addition, ischemia impacts catabolism of adenine
nucleotides, resulting in the accumulation of hypoxanthine in cells. Cytosolic calcium
elevation promotes various pathways, such as activation of phospholipases and impor-
tantly the release of prostaglandins, lipases, proteases and endonucleases, which damages
structural elements of cells [41]. In addition, after increased expression of proinflammatory
gene products in the endothelium (leukocyte adhesion molecules, cytokines, endothelin
thromboxane A2) a proinflammatory state is observed. In contrast, prostacyclin and nitric
oxide are suppressed.

5. Hyperventilation/Hypoventilation
One of the most powerful factors affecting cerebral perfusion is hyperventilation/
hypoventilation, with an effect on CBF and PaCO2 . Hyperventilation is a common therapy
used to reduce elevated ICP or to relax a tense brain (hypocapnia-reduced CBF and CBV).
In traumatic brain injury (TBI) patients, hyperventilation generates a 34% decrease in CBF
and a 9% reduction in cerebral blood volume (CBV) when PaCO2 is decreased from 40 to
30 mmHg [42]. However, hyperventilation and hypocapnia, apart from vasoconstriction
and decreased CBF, also cause neuronal excitability and a longer duration of seizure eleva-
tion, an increase in excitatory amino acids and alkalosis of cerebrospinal fluid with a left
shift in the oxygen–hemoglobin dissociation curve (OHDC) [43,44]. All these mechanisms
may predispose to reduction in oxygen supply and delivery and a significant increase in
oxygen extraction.
It should be noted that carbon dioxide is a common molecule with a physiological
range of 35–45 mmHg. Hypocapnia (partial pressure of carbon dioxide <35 mmHg) and
mild hypercapnia (>45 mmHg) generate important nervous system disturbances. Recent
data have documented that hypercapnia presents neuroprotective mechanisms and may
improve CBF through cerebral vasodilatation. Hypercapnia also leads to brain edema,
elevated ICP, a right shift in the oxyhemoglobin dissociation curve, reduction of systemic
vascular resistance (SVR) and an increase in the tissue oxygen availability [45,46].
J. Pers. Med. 2022, 12, 1763 5 of 20

Hyperventilation is a double-edged sword with some short-term beneficial effects and

longer-term risks. The initial PaCO2 value in TBI in patients with normal ICP should be
within the normal range of 38–42 mmHg. Controlled hyperventilation during mechanical
ventilation in TBI patients (never below PaCO2 of 30 mmHg) is an approved therapeutic,
temporary (during the first 24 h after injury) life-saving intervention in severe intracranial
hypertension [46]. However, PaCO2 levels should be regulated and individualized in every
patient using multimodal neuromonitoring methods [11,47].

6. A Brief Search for “4-H” Factors Affecting CRMO2 and Cellular Oxygen Balance
Brain cells are especially susceptible to ischemic damage because of several unusual
features of their energy metabolism, high metabolic rate, restricted intrinsic energy stores
and critical relationship with the aerobic metabolism of glucose. Therefore, cell metabolism
and the consumption of crucial compounds can be altered by drugs or clinical status, which
can be summarized as “4-H”.

6.1. Hypoxia
The brain is one of the most sensitive organs to hypoxia, reoxygenation and oxidative
stress. As mentioned above, the brain has very high metabolic oxygen requirements, and it
is highly susceptible to hypoxic damage (Table 1).

Table 1. Potentially effect of disorders in oxygen delivery to the brain on selected pathways and
factors. Up arrows indicate the direction of the mechanism that may be intensified to varying degrees,
depending on the causative factor. The number of arrows defines the intensity of the processes.

Hypoxia Normoxia Hyperoxia

Oxidative stress ↑↑ ↑ ↑↑↑
Hypoxia-inducible factor
↑↑ ↑ ↑↑
(HIF)
Protein kinase B
↑↑ ↑ ↑↑
(Akt)
Extracellular signal-regulated
kinase ↑↑ ↑ ↑↑
(ERK)
Brain-derived neurotrophic
factor ↑↑ ↑ ↑↑
(BDNF)
Erythropoietin
↑↑ ↑ ↑↑
(Epo)
Neuroglobin
↑↑ ↑ ↑↑
(Ngb)
Nitric oxide (NO) ↑↑ ↑ ↑↑

Oxidative stress in mitochondria occurs in the state of redox imbalance and small
oxidant patterns such as superoxide radical, hydroxyl radical or nitric oxide radicals are
accumulated. It should be noted that both hypoxia and hyperoxia may induce oxida-
tive stress and apoptosis [48–50]. Acute hypoxia elevates ROS production in the brain,
and reoxygenation promotes this process. A low oxygen level leads to increased lipid
J. Pers. Med. 2022, 12, 1763 6 of 20

peroxidation, protein oxidation and nitric oxide levels and antioxidant defense systems.
Superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GPx)
and reduced/oxidized glutathione (GSH/GSSG) ratio) are significantly inhibited in brain
cells. One of the crucial regulators of oxygen homeostasis and angiogenesis control in a
hypoxic state are HIFs (hypoxia-inducible factors). There are three transcription factors,
HIF-1, HIF-2 and HIF-3 [51]. These heterodimers are expressed by β subunits (HIF-1β,
HIF-2β and HIF-3β) and connected with α subunits, HIF-1α, HIF-2α and HIF-3α, directly
influencing hypoxia. The HIF-1 and HIF-2 are transcriptional regulators with unique target
genes. HIF-1 regulates the acute response to hypoxia (<24 h), and the network formatted
by HIF-1 predisposes to elevated perfusion and an increased oxygen level [52].
PaO2 has little effect on global CBF as long as it does not fall below 50 mmHg [53]. At
this point, there is a dramatic increase in blood flow with a further deterioration in PaO2 [53].
Reduction of ATP levels during hypoxia opens KATP channels on smooth muscle and causes
hypopolarization and vasodilatation [54]. Importantly, hypoxia further decreases PaO2 ,
and CBF may increase by up to 400% of the baseline level [55]. Changed CBF does not
affect metabolism, but hemoglobin saturation decreases from 100% (at PaO2 > 70 mmHg
(PaO2 > 9.33 kPa)) to 50% (at <50 mmHg (at <6.66 kPa)) [55]. In addition, the decrease
in PaO2 increases the production of local NO and adenosine. Chronic hypoxia increases
CBF by affecting capillary density [56,57]. Energy cell failure and delayed apoptosis are
connected with NO•, catalyzed by stimulation of nitric oxide synthase (nNOS) by lactic
acidosis and disruption of ionic transport [58,59].
In addition, neuronal membrane conversion leads to the release of glutamate, which
promotes activation of N-methyl-D-aspartate (NMDA) receptors and calcium influx pro-
moting lipases, proteases and endonucleases, precipitating free radical formation [59,60].
Finally, inflammation, critical mitochondrial dysfunction and ROS (superoxide, hydroxyl,
hydrogen peroxide and other) production with oxidation of lipids, proteins, cells and
deoxyribonucleic acid (DNA) are observed.
In animal models, oxidative stress parameters and the antioxidant system return to
the control system 24 h post brain injury [61]. Coimbra-Costa et al. documented that after
24 h of reoxygenation, oxidative stress is reduced, but apoptosis is preserved, especially
in the hippocampus [62]. The apoptotic rate in the hippocampus being higher than in the
cortex may be the reason for impairment of brain functions in hypoxic brain damage [63].
One of the crucial regulators of oxygen homeostasis and angiogenesis under a hypoxic
state are hypoxia-inducible factors (HIFs) [64]. The HIF-1 binds to hypoxia-responsive
elements (HRE) on gene promoters in the nucleus and promotes transcription of target
genes such as vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT1)
and others such as glycolysis enzymes, lactate dehydrogenase or erythropoietin [65–67].
HIF-1 is also crucial in glycolysis upregulation in astrocytes and Schwann cells [68]. In
contrast, HIF-2 and HIF-3 expressions start under chronic hypoxia in the endothelium.
Importantly, the switch from HIF-1 to HIF-2 and HIF-3 is observed during the adaptation
of the endothelium to prolonged hypoxia. HIF-1 covers the angiogenesis by formation of a
primary and very primitive network, and later expression of HIF-2 and HIF-3 stabilizes
and promotes maturation of this vasculature [69]. In addition, the network formatted by
HIF-1 predisposes to elevated perfusion and increased oxygen level [52].
Another mechanism under chronic hypoxia, which advances proteasomal degrada-
tion, is based on the carboxyl terminus of the Hsp70-interacting protein (Hsp70/CHIP
complex) [70]. The receptor for activated kinase C1 (RACK1) also leads to degradation
of HIF-1α and promotion of heat shock protein 90 (Hsp90), which secures the α sub-
unit [71,72]. Furthermore, RACK1 generates proteasomal degradation and ubiquitination
of HIF-1α [73]. Moreover, Kruppel-like factor 2 (KLF2), expressed in endothelial cells and
responsible for physiological vascularity formation, activates HIF-1 hypoxic degradation in
“a von Hippel–Lindau-independent, but proteasome-dependent manner” via interruption
of the connection Hsp90 with HIF-1 [74,75].
J. Pers. Med. 2022, 12, 1763 7 of 20

MicroRNA (miRNAs) is a family of noncoding RNA molecules with 18–22 nucleotides [76].
There is growing interest in the critical role of miRNA in the development and functioning
of the central nervous system as a gene regulator in “cleaving and silencing the gene expres-
sion” [77]. In contrast, atypical levels of miRNA are documented in various neurological
disorders [78]. The miRNA 210 is mainly expressed in a hypoxic state and is promoted by
HIF1 α and establishes a neuroprotective effect in hypoxia–ischemia damage [79,80].
The miRNA molecules decrease the apoptotic processes of neuronal cells with inhibi-
tion of caspases [81,82]. Therefore, with the growing interest in the association of miRNA
patterns with hypoxia/ischemia, these molecules may be clinical biomarkers for ischemia
and an individual miRNA therapeutics complex [83]. The protective effect of glucocorti-
coids (GCs) under hypoxia and ischemia/reperfusion has been shown recently [84]. GC
administration leads to increased tolerance to hypoxia in the central nervous system [85,86].
Acute hypoxia activates hypothalamic–pituitary–adrenal (HPA) with accumulation of up
to 24 h of corticosterone in serum [85]. Recent data have shown that hypoxic tolerance is
connected with upregulation of HIF-1 α and increased release of GC [85,87]. Direct crosstalk
between GC receptors and HIF-1 is potentially a basis of the biochemical pathways for GC
upregulation of HIF-1 target genes [88–90].
Clinical implications of hypoxia:
• Reduced brain tissue oxygenation is a predictor of poor outcome following severe
traumatic brain injury.
• Hypoxic–ischemic brain injury (HIBI) is associated with significant mortality and
morbidity [91].
• The LOCO2 study documented that targeting lower PaO2 improves outcomes in
patients with acute respiratory distress syndrome (ARDS) [92].
• The brain tissue oxygen tension (PbtO2 ) is crucial, the second monitored variable after
ICP, representing multimodality monitoring in TBI patients [11,93].
• Secondary hypoxia is connected with extended production of cytokines in CSF and
superior elevation of serum biomarkers such as myelin-basic protein (MBP) and
S100 [94].
• The MBP, S100 and neuron-specific enolase (NSE) biomarkers are more elevated in
patients with hypoxia and unfavorable outcomes (Extended Glasgow Outcome Coma
Score (GOSE) 1–4) [94]
• HIBI, as a two-hit model, is an effect of primary and secondary ischemic/hypoxic
damage predisposing to overall devastating severe injury of neurovascular units [91]
• Secondary brain hypoxia is connected with de novo neuronal and astroglial injury.
Importantly, secondary hypoxia is associated with cerebral proinflammatory response
but not parallel cerebral endothelial injury [91].
• Protocols based on PbtO2 and ICP monitoring significantly decrease cerebral hypoxia
time after TBI [95].
• Acute intermittent hypoxia (AIH) and task-specific training (TST) may synergistically
improve motor functions after central nervous system injury [96].

6.2. Hyperoxia
The concept of hyperoxia toxicity is defined by endogenous production of ROS [48,97].
Experimental examination of mitochondrial structure after 100% oxygen therapy
showed swollen and huge mitochondria and diluted and damaged mitochondria mem-
branes and cristae, which were directly connected with myelin, axonal and cellular or-
ganelle injury in the cortical brain [98]. Hyperoxia is connected with inhibition of Akt
expression and/or phosphorylation, the reverse of low oxygen levels [99,100]. Experi-
mental research has documented that in rat models of hyperoxia (FiO2 0.4–0.8), p-Akt
expression decreases steadily, over time until 12 h, then reverses to baseline value [100,101].
Thus, Akt signaling increases in hypoxia and is depressed in hyperoxia [102].
Mitogen-activated protein kinases (MAPKs) are involved in the PI3K-Akt signaling
pathway, an important pathway with a neuroprotective role against hypoxia or oxidative
J. Pers. Med. 2022, 12, 1763 8 of 20

stress [103]. Recent data on rat models showed that hyperoxia (FiO2 0.4–0.8) decreases the
p-ERK1/2 activation until 12 h and is followed by recovery in the subsequent 12 h [101].
Furthermore, hyperoxia in rat brain models impacts BDNF and neurotrophins 3 and
4 downregulation, and proceeds with correction in the subsequent 15–20 h, predispos-
ing to hyperoxia-linked apoptotic neurodegeneration [101,104]. Erythropoietin receptor
(EpoR) binding, observed in different brain areas, also plays an important role in oxygen
metabolism [105]. Under hypoxia, it is upregulated because HIF-1α binds to the Epo, show-
ing a neuroprotective effect contrary to ischemia hypoxia/reoxygenation injury [106–108].
Experimental data showed that hyperoxia upregulates Epo in mice treated with FiO2 0.5
for 3 weeks, elevating HIF-2α, but during 4 weeks of treatment with FiO2 = 0.3, only
EpoR expression increases [100]. Noteworthy is NO, which ameliorates oxygen delivery by
improving cerebral blood flow in the microvasculature [109]. In addition, NOS presents
a neuroprotective effect by improving vessel autoregulation [110]. It triggers different
mechanisms such as BDNF expression, HIF stabilization, S-nitrosylation of the HIF, block-
ing HIF-1α degradation, interaction with MAPK and phosphoinositide 3-kinase (PI3K)
signaling, and EpoR expression upregulation [111–116]. In a nonphysiological state pre-
senting hyperactivity of selected NOS, the NO starts to be neurotoxic as a free radical [109].
High oxygen concentration controls NOS expression and inhibits NO via surplus release
of superoxide anions inhibiting NO vasorelaxation and promoting vasoconstriction in the
brain [117,118]. Importantly, the connection of superoxide anions with NO promotes per-
oxynitrite (ONOO−) production with destructive properties [119–121]. In animal research,
NO is connected with hyperoxia-induced proliferation and proinflammatory responses in
astrocytes via cyclooxygenase-2 and prostaglandin E2 suppression [122].
Clinical implications of hyperoxia:
• Hyperoxia is associated with higher mortality and worse short-term functional out-
comes, especially in patients who receive uncontrolled oxygen delivery during the first
24 h after brain injury (probably because of hyperoxia-induced oxygen-free radical
toxicity with or without vasoconstriction) [123].
• Potential toxicity of a high oxygen concentration (patients receiving FiO2 of more
than 0.6).
• Previous studies documented that higher inspired oxygen concentration is associated
with acute lung injury, with mild to severe diffuse alveolar damage (DAD) [124].
• High oxygen levels within 72 h after aneurysmal rupture is an uninfluenced predictor
of cerebral vasospasm [125].
• In addition, liberal oxygen therapy increased 30-day mortality compared with conser-
vative therapy [126].
• Controversial high-dose oxygen therapy recommendations to reduce surgical site
infections (SSIs) by World Health Organization global guidelines for the prevention of
surgical site infection [127].
• Hyperoxemia may reduce cardiac output and increase systemic vascular resistance in
patients with cardiovascular failure [128].

6.3. Hyperthermia
Increased body temperature is frequently observed in patients following brain dam-
age due to direct hypothalamic injury, cerebral inflammation or secondary infection
indicating fever.
Systemic hyperthermia is common after brain damage. In patients with brain injury, it
is associated with poor neurological outcomes because it predisposes to worse secondary
damage [129] (Figure 2).
J. Pers. Med. 2022, 12, 1763 9 of 20

Figure 2. Hyperthermia is associated with poor neurological outcomes because it predisposes

to greater secondary damage. Temperature changes lead to elevation of cytokine release, higher
neutrophil activity and elevated metabolic expenditure. Hyperthermia also increases ROS generation
and apoptosis.

It should be noted that hyperthermia is not always connected with fever. Fever is an
adaptive reaction with, e.g., elevated neutrophil migration, activation of T-lymphocytes
and increased interleukin-1 and interferon production [130]. Temperature changes lead
to elevated cytokine release, higher neutrophil activity and elevated metabolic expendi-
ture, elevated white blood cell accumulation, increased vascular permeability, and axonal
damage [129]. Temperature changes also lead to cerebral blood flow conversion and hence
cause changes to cerebral oxygenation. Recent animal research has documented that
hyperthermia is associated with CD18 and intercellular adhesion molecule-1 (ICAM-1)
activation, as well as with an increase in ionized calcium-binding adapter protein-1 (IBA-1)
reactive microglia in the cortex [131]. Hyperthermia also increases ROS generation and
apoptosis, for example by c-Jun N-terminal kinase (JNK) activation [132,133]. Wettervik
et al. documented that hyperthermia leads to energy metabolism disturbances with no
associations with higher ICP and lower CPP [134]. Importantly, higher temperature was
connected with lower glucose concentration in cerebral tissue and a higher percentage of
the lactate-pyruvate ratio >25 after 5 days [134]. In addition, the authors did not show a
connection between hyperthermia and worse clinical outcomes.
The metabolic rate rises by around 20–25% during increased baseline core temperature
of over 1.5–2 ◦ C [135]. Recent data have shown that rising core temperature impacts
increased cerebral glucose utilization and CMRO2 by 5 to 10% per degree Celsius [136].
Nunneley et al. observed that a temperature elevated by more than 2 ◦ C is associated
with a higher glucose metabolic rate in the hypothalamus, thalamus, corpus callosum,
cingulate gyrus and cerebellum and lower in the caudate, putamen, insula and posterior
cingulum [137]. In addition, an increase in brain metabolism by 10% following a 2 ◦ C
higher temperature may be connected with an important reduction of blood flow to support
oxygenation [137]. Further, Spiotta et al. documented that hyperthermia did not reduce
brain tissue oxygen [138]. It should be noted that higher body temperature leads to a better
ability to maintain O2 uptake (VO2 ) because a higher fraction of the delivered O2 is extracted
J. Pers. Med. 2022, 12, 1763 10 of 20

before the beginning of O2 supply subjection [139]. Cardiovascular adjustments, as well as

sympathetic nerve activity during hyperthermia, also impact coupling between CMRO2 and
CBF. The activity of sympathetic nerves increases under hyperthermia. Adrenergic nerves
surround the vascular system, especially cerebral arteries [140]. Some authors suggest that
vasoconstriction under hyperthermia causes decreased CBF [141]. However, there are a
few doubts. First, in a hypermetabolic state under hyperthermia, different agents such as
histamine, nitric oxide or prostanoids may counteract vasoconstriction [142]. Second, blood
pressure significantly influences the cerebral vascular system. Third, the heterogenous
response of cerebral vascularity may be modified by hyperthermia and changes in the
density of alpha- and beta-adrenergic receptors [143]. Elevated body temperature impairs
blood–brain barrier (BBB) integrity, especially with dehydration [144,145]. Finally, Bein
et al. documented that the normalization of PaCO2 to eucapnia leads CBF to recuperate to
a physiological state [18].
Clinical implications of hyperthermia:
• Systemic complications such as fever frequently occur in the early phase after brain
damage and worsen secondary brain injury [134,146].
• Up to 50% of patients after acute brain injury experience fever during hospitalization [147].
• Brain temperature variations (>1 ◦ C) are associated with poor functional outcomes [148].
• In sum, higher body temperature is associated with elevated metabolic demand and
endogenous stress levels, blood pressure level changes, increases in cardiac output and
heart rate, hyperventilation, the synaptic release of excitatory amino acids, increased
ICP levels, ischemic cortical depolarizations, and BBB breakdown [146,149–154].
• Hyperthermia without oxygen delivery mismatch does not seem to induce significant
neurochemical alterations such as glucose, lactate, pyruvate and glutamate levels [151].
• PbtO2 may be an important element to be monitored during a high body temperature
episode to provide a view into oxygen metabolism in the brain [155].
• PbtO2 variations are observed under increased temperature increases in severe TBI
patients. PbtO2 may rise on average in every third and decrease in every sixth episode
of high temperature. Recent data have documented that the PbtO2 slope may occur
simultaneously with CPP and MAP reduction [156].
• Temperature management to prevent fever is crucial for patients with severe trau-
matic brain injury. The international guidelines for severe brain injury highlight the
importance of core temperature measurement and treatment above 38 ◦ C [11,46].

6.4. Hypothermia
The main objective of current international clinical guidelines is to ameliorate final
outcomes by inhibiting secondary injury, especially in the acute phase after damage. These
protocols also include correction of temperature and therapeutic hypothermia. Moderate
to deep hypothermia suppresses inflammation and decreases excitotoxicity and the pro-
duction of free radicals, which is one of the mechanisms of neuroprotection [157]. Different
levels of hypothermia improve neuronal tolerance to ischemia and inhibited neuronal
death [158,159]. Cerebral hypothermia decreases ICP, maintains BBB function and ame-
liorates glucose utilization [160–163]. In addition, lower temperature suppresses hypoxic
brain depolarization, releases neurotransmitters and decreases metabolism by protease
activation and a high energy phosphate depletion rate [164,165]. Authors have even noted
that deep hypothermia affects cerebral ATP production and improves survival after cardiac
arrest by three to four times [164]. Importantly, hypothermia during ischemia reduces
lipid peroxidation and essentially decreases ROS production [159,166]. Hypothermia re-
duces JNK activation and the apoptotic rate [132]. Hypothermia also activates a cascade
of neuroinflammation and may improve M1/M2 macrophage polarization to a favorable
phenotype [167].
Lower temperature improves cerebral metabolism after TBI and cerebral ischemia.
In animal models, the metabolic rate for glucose (CMRglc ) and CMRO2 is decreased, but
significantly, ATP distribution is decreased more than synthesis is [168]. Furthermore,
J. Pers. Med. 2022, 12, 1763 11 of 20

under a normoxic state, hypothermia decreases oxygen consumption in the brain as well as
collateral depletion of CBF and delivery of oxygen (elevated cerebrovascular resistance and
trace changes in oxygen extraction in the brain) [169]. Temperate hypoxia causes elevated
CBF and oxygen extraction, followed by reduced cerebrovascular resistance [170]. Chihara
et al., in an animal model of reduction in cerebral temperature by 1.6◦ ± 0.1◦ and hypoxia,
documented that hypothermia results in decreased oxygen delivery, oxygen consumption
and CBF. In addition, a significant improvement in cerebral vascular resistance is observed
as well as no oxygen extraction shift [171]. Recent data by Hashem et al., using near-
infrared spectroscopy (NIRS) and magnetic resonance imaging (MRI) methods, presented a
significant decrease of CMRO2 in the cortex of around 37 and 32% of hypothermic mice and
rats, respectively [172]. Therefore, targeting brain tissue oxygenation by different methods
such as an NIRS device may be an important aspect of brain damage treatment guidelines
for improving cerebral oxygenation, monitoring cerebrovascular reactivity (CVR) and final
outcomes [173,174].
Clinical implications of hypothermia
• Therapeutic hypothermia is a crucial component of current clinical practice guidelines.
• Therapeutic hypothermia uses different cooling methods to maintain brain tempera-
ture at target levels.
• Therapeutic hypothermia improves neurological outcomes [175]. In contrast, acciden-
tal hypothermia at admission after TBI results in higher hospital mortality [176].
• Recently published data do not promote early prophylactic hypothermia within the
first 6 h after damage in TBI patients [177].
• Body temperature of 35 to 35.5 ◦ C after TBI reduces intracranial hypertension and pre-
serves adequate CPP without cardiac dysfunction and oxygen debt [178]. In addition,
hypothermia reduces high ICP [177].
• Recent meta-analyses have documented the importance of temperature measurement
to avoid hypothermia in prehospital management [176].

7. Future Therapies
The oxygen-related mechanisms discussed have been a target for therapy in brain
injuries. One crucial element in the management of patients with various forms of cerebral
damage is the maintenance of oxygen homeostasis, supply and consumption, translating
into normal mitochondrial metabolism. Both hypoxia and hyperoxia may present a negative
effect on the final neurological outcome. Recent findings have shown the role of oxygen
therapy in neuroprotection, related to normobaric hyperoxia (NBHO). Patients with acute
brain injury treated with high oxygen levels (FiO2 0.6–1.0) for two hours presented with
improved redox balance and reduced lactate/pyruvate ratio (∆LPR −3.07 p = 0.015) [179].
The NBHO method is based on continuous administration of oxygen in normal atmospheric
pressure. Experimental data have documented the benefits of NBHO in ischemic stroke,
hemorrhagic strokes and brain trauma [180,181].
Yang et al. in an animal model experimentally documented the effect of normobaric
oxygen therapy (60%) on neurological functions, edema and HIF-1α, aquaporin 4 (AQP4)
and Na+/H+ exchanger 1 (NHE1) expression (p < 0.05, respectively). These authors showed
that therapy inhibits NHE1 expression and Na+ influx. These effects result in the reduction
of brain edema following the movement of water by AQP4 [180]. Hyperbaric oxygen
therapy (HBOT) is another therapy proposed in TBI. HBOT is 100% oxygen inhalation
under a pressure greater than 1 absolute atmosphere. HBOT suppresses inflammation and
defends BBB integrity and supports angiogenesis and neurogenesis [182,183]. Recent data
in an animal model documented that oxygen therapy at an early stage after brain damage
significantly decreased NF -κB and extracellular histones H1, H2A and H4 expression [184].
Histones are structural proteins in nuclei, an important factor in inflammation caused
by hypoxia and ischemia [185]. In addition, HBOT inhibits the apoptotic mechanisms in
neuronal cells and preserves the properties of mitochondrial membranes, reducing sec-
ondary damage [186,187]. Of course, the clinical effectiveness of HBOT is still controversial.
J. Pers. Med. 2022, 12, 1763 12 of 20

Rockswold et al. documented in a small study that HBOT did not improve outcomes in a
group of patients with closed head injury [188]. However, in other phase II clinical trials in
2013, Roackswold et al. demonstrated that combined HBOT with normobaric hyperoxia
(NBHT) therapy improves oxidative metabolism and oxygen brain tissue partial pressure
levels [189]. In addition, this therapy decreased intracranial hypertension, mortality and
improved outcomes (measured by GOSE) [189]. Another study showed that HBOT sig-
nificantly improved post-traumatic stress disorder symptoms, cognitive functions and
decreased depression and anxiety [190].
The controversial effects of HBOT may be explained by the hyperoxic–hypoxic paradox
(HHP). Recent research has shown that repetitive and periodic hyperoxia may induce
molecular mechanisms and activate mediators similarly to hypoxia [191]. Activation of
HIF, VEGF, SIRT, mitochondrial biogenesis and stem cell proliferation is observed during
intermittent hyperoxia.
Another therapeutic option is the significant role of lactate in cerebral energy
metabolism [192]. Experimental lactate supplementation in ischemic brain damage impacts
decreased glutamate- and gamma-aminobutyric acid (GABA) release with improvement
in electroencephalogram (EEG) [193]. Furthermore, Berthet et al. documented that lactate
supplementation inhibits neuronal death in oxygen and glucose delivery disturbances [194].
The same treatment in middle cerebral artery occlusion and ischemia models also presents
a significant neuroprotective effect [195,196]. Ichai et al., in randomized controlled trials,
presented that hypertonic sodium lactate (HSL) treatment is more potent in reducing ele-
vated ICP than mannitol in a group of TBI patients [197]. In addition, this effect lasts longer
and is connected with improvement in jugular venous O2 saturation, glucose and lactate
levels in plasma and pH. Patients also presented better neurological final outcomes [197].
The infusion of HSL for 3 h impacts extracellular metabolites. One theory is that these
solutions contain metabolizable lactate and Na ions. Lactate in the brain induces an imbal-
ance between anions and positive charges and counteracts the harmful cellular swelling by
compensation of anion efflux [197] (Supplementary Materials).
Recent data have shown elevated lactate, pyruvate and glucose levels in the brain with
associated lower glutamate and PbtO2 values as well as ICP. Bouzat et al. documented that
these effects may be the result of a brain metabolism shift to elevated lactate utilization,
sparing the effect of glucose. In addition, the inhibition of cerebral oxygenation may be
secondary to alkalosis, which increases the affinity of oxygen to hemoglobin and suggests a
beneficial effect [198]. In summary, hypertonic sodium lactate infusion reduces glutamate-
related excitotoxicity, improves cerebral perfusion, buffers metabolic acidosis, decreases
cerebral edema and ICP and improves cardiac performance [199–201].

8. Conclusions
Oxygen is crucial for the functionality of cerebral cells. Therefore, the mechanisms
leading to disruption of oxygen supply and consumption are the subject of continuous
intensive research. There is a growing need for novel therapeutic methods to reduce the
cascade of pathological cellular processes.

Supplementary Materials: The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/jpm12111763/s1, Table S1: Novel therapy approaches.
Author Contributions: Conceptualization, C.R. and D.S.-G.; methodology, D.S.-G. and C.R.; valida-
tion, C.R., W.D. and D.S.-G.; formal analysis, D.S.-G.; writing—original draft preparation, D.S.-G.;
writing—review and editing, C.R., D.S.-G., W.D., J.G. and R.B.; visualization, D.S.-G., W.D., C.R. and
J.G.; supervision, D.S.-G., C.R., W.D. and R.B.; project administration, D.S.-G. All authors have read
and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
J. Pers. Med. 2022, 12, 1763 13 of 20

Data Availability Statement: Not applicable.

Conflicts of Interest: The authors declare no conflict of interest.

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